Highly Enantioselective Hydrogenation of α-Arylmethylene Cycloalkanones Catalyzed by Iridium Complexes of Chiral Spiro Aminophosphine Ligands

Article abstract of DOI:10.1021/ja100652f

The highly efficient asymmetric hydrogenation of α-arylmethylene cycloalkanones catalyzed by Ir-complexes of chiral spiro aminophosphine ligands was developed, providing chiral exo-cyclic allylic alcohols at high yields with excellent enantioselectivities (up to 97% ee) and high turnover numbers (S/C up to 10,000). This new reaction provided an efficient method for the synthesis of the key intermediate of the active form of the anti-inflammatory loxoprofen.

Full text of DOI:10.1021/ja100652f

Published on Web 03/16/2010
Highly Enantioselective Hydrogenation of r-Arylmethylene Cycloalkanones
Catalyzed by Iridium Complexes of Chiral Spiro Aminophosphine Ligands
Jian-Bo Xie, Jian-Hua Xie,* Xiao-Yan Liu, Wei-Ling Kong, Shen Li, and Qi-Lin Zhou*
State Key Laboratory and Institute of Elemento-organic Chemistry, Nankai UniVersity, Tianjin 300071, China
Received January 25, 2010; E-mail: qlzhou@nankai.edu.cn; jhxie@nankai.edu.cn
Chiral allylic alcohols are important and versatile intermediates in
organic synthesis because they can be readily converted into a variety
of biologically active molecules, such as pharmaceuticals and natural
products.1 The transition-metal-catalyzed asymmetric hydrogenation
of the carbonyl group of R,ꢀ-unsaturated ketones is a direct method
to produce chiral allylic alcohols.2 The Ir-complexes of phosphine
ligands were the first catalysts used for asymmetric hydrogenation of
R,ꢀ-unsaturated ketones but yield the corresponding chiral allylic
alcohols with low ee values.3 High enantioselectivity (up to 98% ee)
in the hydrogenation of R,ꢀ-unsaturated ketones was obtained by
Noyori et al. using Ru-BINAP/diamine catalysts in 1995.4 Since then,
the catalysts used in the asymmetric hydrogenation of R,ꢀ-unsaturated
ketones to chiral allylic alcohols have been dominated by Ru-
diphosphine/diamine complexes, and various acyclic and endo-cyclic
R,ꢀ-unsaturated ketones have been hydrogenated with good to excellent
enantioselectivities.5 However, the asymmetric hydrogenation of exo-
cyclic R,ꢀ-unsaturated ketones is still a challenge,6 despite the fact
that the corresponding hydrogenation products, exo-cyclic allylic
alcohols, serve as key intermediates for the synthesis of chiral drugs
(e.g., the trinem antibiotic sanfetrinem)6c and natural products (e.g.,
slaframine).6d Thus, the development of highly efficient methods for
the asymmetric synthesis of exo-cyclic allylic alcohols is highly
desirable.
ligands.10 The acids 4 were easily converted to spiro aminophosphine
ligands 3a-f in excellent yields (80-98%) using a Schmidt reaction
(Scheme 2).
Scheme 2. Synthesis of Chiral Spiro Aminophosphine Ligands 3
In the study of Ir-catalyzed asymmetric hydrogenation of R-aryl-
methylene cycloalkanones 1, we initially chose (E)-R-benzylidene
cyclohexanone (1a) as a model substrate and performed the hydro-
genation in 1-propanol containing KOtBu under 6 atm of H2 with the
catalyst Ir-(R)-3 generated in situ from 0.05 mol % [Ir(COD)Cl]2 and
0.12 mol % ligand (R)-3. A comparison of ligands showed that the
ligand (R)-3e, which has bulky 3,5-di-tert-butylphenyl groups on the
P-atom, gave the highest activity and enantioselectivity. The reaction
was completed within 0.5 h and provided the hydrogenation product
(S)-2a at a yield of 98% with 97% ee (Table 1, entry 5). The ligand
(R)-3f with 3,5-di-tert-butyl-4-methoxyphenyl groups on the P-atom
gave a comparable yield and enantioselectivity (entry 6), while the
other ligands yielded (S)-2a in only small amounts with moderate ee
values (entries 1-4). The addition of a strong base, such as KOtBu
and KOH, was required to obtain high activity and enantioselectivity.
No reaction was observed in the absence of hydrogen gas, which
indicated that hydrogenation instead of transfer hydrogenation occurred
in the reaction. Solvent experiments showed that both nPrOH and EtOH
Scheme 1. Asymmetric Hydrogenation of exo-Cyclic
R,ꢀ-Unsaturated Ketones
i
were good solvents for this reaction, but MeOH and PrOH were
inferior, offering lower yields and ee values (entries 9 and 11). The
ratio of Ir/L was also investigated, and the results showed that one
Table 1. Asymmetric Hydrogenation of 1a Catalyzed by Ir-(R)-3a
Recently, we demonstrated that Ru-SDPs/diamine catalysts are
highly efficient for the asymmetric hydrogenation of ketones and
aldehydes,7 providing chiral alcohols with excellent enantioselectivities.
When we attempted to apply these catalysts for the hydrogenation of
exo-cyclic (E)-R,ꢀ-unsaturated ketone 1a (R ) Ph, n ) 2), we obtained
allylic alcohol 2a in low yield with moderate ee.8 To develop efficient
methods for the preparation of enantiomer-enriched exo-cyclic allylic
alcohols, we investigated iridium catalysts and found that the Ir-
complex of spiro aminophosphine ligand (R)-3e is a highly efficient
catalyst for the hydrogenation of (E)-R-arylmethene cycloalkanones
1 (Scheme 1). In this Communication, we report the first highly
enantioselective hydrogenation of (E)-R-arylmethene cycloalkanones
by using chiral Ir-complexes of spiro aminophosphine ligands 3 and
its application in the synthesis of the key intermediate of the active
form of the anti-inflammatory loxoprofen 7.
conv.
(%)b
yield
(%)c
ee
(%)d
entry
ligand
base
solvent
1
2
3
4
5
6
7
8
(R)-3a
(R)-3b
(R)-3c
(R)-3d
(R)-3e
(R)-3f
(R)-3e
(R)-3e
(R)-3e
(R)-3e
(R)-3e
(R)-3e
(R)-3e
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOH
K2CO3
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
nPrOH
nPrOH
nPrOH
nPrOH
nPrOH
nPrOH
nPrOH
nPrOH
MeOH
EtOH
24
36
45
20
100
95
100
100
100
100
100
100
100
23
34
39
18
98
87
95
92
86
93
71
97
91
53
68
71
61
97
94
96
90
89
97
93
96
93
9
10
11
iPrOH
nPrOH
nPrOH
12e
13f
a Reaction conditions: 3.0 mmol scale, [subst] ) 1.5 M, 0.05 mol %
[Ir(COD)Cl]2, 0.12 mol % (R)-3, [Base] ) 0.04 M, 6 atm of H2, 2.0 mL
of solvent, rt, 0.5 h. b Determined by 1H NMR. c Isolated yield.
d Determined by HPLC. e Ir/L ) 1:2. f S/C ) 10 000, 50 atm of H2, 30
°C, 4 h.
Chiral spiro aminophosphine (abbreviated as SpiroAP) ligands 3
were prepared from optically pure 1,1′-spirobiindane-7,7′-diol9 via
bisarylphosphino-7′-carboxy-1,1′-spirobiindanes 4, which was the key
intermediate in our previous synthesis of spiro phosphine-oxazoline
9
4538 J. AM. CHEM. SOC. 2010, 132, 4538–4539
10.1021/ja100652f  2010 American Chemical Society

C O M M U N I C A T I O N S
equivalent ligand is enough to achieve high activity and enantiose-
lectivity, indicating that the active catalyst contains only one amino-
phosphine ligand (entries 5 and 12). The Ir-(R)-3e catalyst had a very
high activity such that the reaction could be performed with as low as
0.01 mol % of catalyst loading.
In conclusion, the highly efficient asymmetric hydrogenation of
R-arylmethylene cycloalkanones was realized by using Ir-complexes
of chiral spiro aminophosphine ligands. This new reaction provides a
practical approach to the synthesis of exo-cyclic allylic alcohols and
ꢀ-arylmethyl cyclic alcohols, including the key intermediate of the
active form of loxoprofen.
As summarized in Table 2, a number of (E)-R-arylmethylene
cyclohexanones 1 can be hydrogenated to the chiral ꢀ-arylmethylene
cyclohexanols 2 in high yields with excellent enantioselectivities
(entries 1-10). Either the electron-donating or electron-withdrawing
substituent on the phenyl ring of the substrate had little effect on both
the reactivity and enantioselectivity of the reaction. When the substrate
with a five-membered ring (1k-m) or a seven-membered ring (1n)
was subjected to the hydrogenation, the corresponding ꢀ-arylmethylene
cyclic alcohols were obtained at 97-98% yields with 93-96%
enantiomeric excesses (entries 11-14). The (E)-R-alkylmethylene
cyclohexanone 1o (R ) Me) could also be hydrogenated to the desired
allylic alcohol 2o with 91% ee, albeit with a lower reaction rate and
yield (entry 15).
Acknowledgment. We thank the National Natural Science
Foundation of China, the National Basic Research Program of China
(973 Program, No 2006CB806106, 2010CB833300), the Ministry of
Health (Grant No 2009ZX09501-017), and the “111” project (B06005)
of the Ministry of Education of China for financial support. Dedicated
to Prof. Albert S. C. Chan on the occasion of his 60th birthday.
Supporting Information Available: Experimental procedures, the
characterizations of chiral ligands and products, and the analysis of ee
values of hydrogenation products (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
Table 2. Asymmetric Hydrogenation of 1 Catalyzed by Ir-(R)-3ea
References
time
(h)
yield
(%)b
ee
(%)c
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1
2
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C6H5
2
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1
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3
2
2a
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95
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98
98
99
98
97
66
97 (S)
95
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94
94
95
95
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89
93
96
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94 (S)
93
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
3-MeOC6H4
2-MeOC6H4
2-Furyl
1-naphthyl
2-naphthyl
C6H5
9
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13
14
15
4-MeOC6H4
4-BrC6H4
C6H5
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Me
91
a Reaction conditions are the same as those in Table 1, entry 5.
b Isolated yield. c Determined by GC or HPLC.
To demonstrate the utility of this asymmetric hydrogenation, we
studied the synthesis of (1S,2R)-6, a key intermediate in the preparation
of the active form of the anti-inflammatory loxoprofen 7 (Scheme 3).
Recently, Kobayashi et al. reported the synthesis of (1S,2R)-6 with an
85% yield by a five-step procedure, starting from optically pure
(1R,4S)-4-hydroxycyclopent-2-enyl acetate, in the total synthesis of
the active form of loxoprofen 7.11 We performed the hydrogenation
of (E)-2-(4-bromobenzylidene)cyclopentanone (1m) with 0.02 mol %
Ir-(R)-3e as catalyst (S/C ) 5000) under the standard conditions and
obtained allylic alcohol (S)-2m at a yield of 97% with 93% ee. The
ee value of (S)-2m was further improved to 99% by recrystallization
from ethyl acetate/petroleum ether. The reduction of (S)-2m with
LiAlH4 yielded alcohol (1S,2R)-5 at 95%, and its absolute configuration
was determined by X-ray structure analysis (see Supporting Informa-
tion). The hydroxyl group of (1S,2R)-5 was protected with tert-
butyldimethylsilyl chloride to yield (1S,2R)-6 at 95%. Thus, (1S,2R)-6
was prepared with a yield of 77% in three steps from an achiral starting
material.
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Scheme 3. Enantioselective Synthesis of (1S,2R)-6
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with 32% ee was obtained.
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